Substituted porphyrins

ABSTRACT

The present invention relates, in general, to a method of modulating physiological and pathological processes and, in particular, to a method of modulating cellular levels of oxidants and thereby processes in which such oxidants are a participant. The invention also relates to compounds and compositions suitable for use in such methods.

RELATED APPLICATIONS

This application is a divisional application of application Ser. No.10/349,171, filed Jan. 23, 2003, which is a continuation of applicationSer. No. 09/490,537, filed Jan. 25, 2000, which claims priority to U.S.Provisional Application No. 60/117,010, filed Jan. 25, 1999, which isincorporated herein by reference in its entirety.

This invention was made with Government support under Grant Nos. HL31992and HL63397 awarded by the National Institutes of Health. The Governmenthas certain rights in the invention.

TECHNICAL FIELD

The present invention relates, in general, to a method of modulatingphysiological and pathological processes and, in particular, to a methodof modulating cellular levels of oxidants and thereby processes in whichsuch oxidants are a participant. The invention also relates to compoundsand compositions suitable for use in such methods.

BACKGROUND

Oxidants are produced as part of the normal metabolism of all cells butalso are an important component of the pathogenesis of many diseaseprocesses. Reactive oxygen species, for example, are critical elementsof the pathogenesis of diseases of the lung, the cardiovascular system,the gastrointestinal system, the central nervous system and skeletalmuscle. Oxygen free radicals also play a role in modulating the effectsof nitric oxide (NO.). In this context, they contribute to thepathogenesis of vascular disorders, inflammatory diseases and the agingprocess.

A critical balance of defensive enzymes against oxidants is required tomaintain normal cell and organ function. Superoxide dismutases (SODs)are a family of metalloenzymes that catalyze the intra- andextracellular conversion of O₂ ⁻ into H₂O₂ plus O₂, and represent thefirst line of defense against the detrimental effects of superoxideradicals. Mammals produce three distinct SODs. One is a dimeric copper-and zinc-containing enzyme (CuZn SOD) found in the cytosol of all cells.A second is a tetrameric manganese-containing SOD (Mn SOD) found withinmitochondria, and the third is a tetrameric, glycosylated, copper- andzinc-containing enzyme (EC—SOD) found in the extracellular fluids andbound to the extracellular matrix. Several other important antioxidantenzymes are known to exist within cells, including catalase andglutathione peroxidase. While extracellular fluids and the extracellularmatrix contain only small amounts of these enzymes, other extracellularantioxidants are also known to be present, including radical scavengersand inhibitors of lipid peroxidation, such as ascorbic acid, uric acid,and ∀-tocopherol (Halliwell et al., Arch. Biochem. Biophys. 280:1(1990)).

The present invention relates generally to low molecular weightporphyrin compounds suitable for use in modulating intra- andextracellular processes in which superoxide radicals, or other oxidantssuch as hydrogen peroxide or peroxynitrite, are a participant. Thecompounds and methods of the invention find application in variousphysiologic and pathologic processes in which oxidative stress plays arole.

SUMMARY OF THE INVENTION

The present invention relates to a method of modulating intra- orextracellular levels of oxidants such as superoxide radicals, hydrogenperoxide, peroxynitrite, lipid peroxides, hydroxyl radicals and thiylradicals. More particularly, the invention relates to a method ofmodulating normal or pathological processes involving superoxideradicals, hydrogen peroxide, nitric oxide or peroxynitrite using lowmolecular weight antioxidants, and to methine (i.e., meso) substitutedporphyrins suitable for use in such a method.

Objects and advantages of the present invention will be clear from thedescription that follows.

BRIEF DESCRIPTION OF THE DRAWING

FIGS. 1A-C show the structures of certain compounds of the invention.The SOD activity values were determined using the method of McCord andFridovich, J. Biol. Chem. 244:6049 (1969). The catalase values weredetermined using the method of Day et al., Arch. Biochem. Biophys.347:256 (1997). The TBARS values were obtained as follows:

Homogenates

Frozen adult Sprague-Dawley rat brains, livers and mouse lungs(Pel-Freez, Rogers, Ark.) were homogenized with a polytron (Turrax T25,Germany) in 5 volumes of ice cold 50 mM potassium phosphate at pH 7.4.Homogenate protein concentration was determined with the Coomassie Plusprotein assay (Pierce, Rockford, Ill.) using bovine serum albumin as astandard. The homogenate volume was adjusted with buffer to give a finalprotein concentration of 10mg/ml and frozen as aliquots at −80° C.

Oxidation of Homogenates

Microfuge tubes (1.5 ml) containing 0.2 ml of homogenate (0.2 mgprotein) and various concentrations of antioxidant were incubated at 37°C. for 15 minutes. Oxidation of the rat brain homogenate was initiatedby the addition of 0.1 ml of a freshly prepared stock anaerobic solutioncontaining ferrous chloride (0.25 mM) and ascorbate (1 mM). Samples wereplaced in a shaking water bath at 37° C. for 30 minutes (final volume 1ml). The reactions were stopped by the addition of 0.1 μL of a stockbutylated hydroxytoluene (60 mM) solution in ethanol.

Lipid Peroxidation Measurement

The concentration of thiobarbituric acid reactive species (TBARS) in ratbrain homogenates was used as a index of lipid peroxidation.Malondialdehyde standards were obtained by adding 8.2 μL of1,1,3,3-tetramethoxypropane in 10 ml of 0.01 N HCl and mixing for 10minutes at room temperature. This stock was further diluted in water togive standards that ranged from 0.25 to 25 μM. Samples or standards (200μL) were acidified with 200 μL of 0.2 M stock of phosphoric acid in 1.5ml locking microfuge tubes. The color reaction was initiated by theaddition of 25 μL of a stock thiobarbituric acid solution (0.11 M) thatwas mixed and then placed in a 90° C. heating block for 30 minutes.TBARS were extracted with 0.5 ml of n-butanol by vortexing for 3 minutesand chilling on ice for 1 minute. The samples were then centrifuged at12,000×g for 3 minutes and a 150 μL aliquot of the n-butanol phase wasplaced in each well of a 96-well plate and read at 535 nm in a Thermomaxplatereader (Molecular Devices, Sunnydale, Calif.) at 25° C. Sampleabsorbances were converted to MDA equivalences (μM) by extrapolationfrom the MDA standard curve. None of the antioxidants at concentrationsemployed in these studies affected the reaction of MDA standards withthiobarbituric acid.

Statistical Analyses

Data were presented as their means ± SE. The inhibitory concentration ofantioxidants that decreased the degree of lipid peroxidation by 50%(IC₅₀) and respective 95% confidence intervals (CI) were determined byfitting a sigmoidal curve with variable slope to the data (Prizm,GraphPad, San Diego, Calif.). (See also Braughler et al., J. Biol. Chem.262:10438 (1987); Kikugawa et al., Anal. Biochem. 202:249 (1992).)

FIG. 2 shows the data obtained from a study involving treatment ofbronchopulmonary dysplasia using Aeol-V.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to methods of protecting against thedeleterious effects of oxidants, particularly, superoxide radicals,hydrogen peroxide and peroxynitrite, and to methods of preventing andtreating diseases and disorders that involve or result from oxidantstress. The invention also relates methods of modulating biologicalprocesses involving oxidants, including superoxide radicals, hydrogenperoxide, nitric oxide and peroxynitrite. The invention further relatesto compounds and compositions, including low molecular weightantioxidants (e.g., mimetics of scavengers of reactive oxygen species,including mimetics of SODs, catalases and peroxidases) and formulationsthereof, suitable for use in such methods.

Mimetics of scavengers of reactive oxygen species appropriate for use inthe present methods include methine (i.e., meso) substituted porphines,or pharmaceutically acceptable salts thereof (e.g., chloride or bromidesalts). The invention includes both metal-free and metal-boundporphines. In the case of metal-bound porphines, manganic derivatives ofmethine (meso) substituted porphines are preferred, however, metalsother than manganese such as iron (II or III), copper (I or II), cobalt(II or III), or nickel (I or II), can also be used. It will beappreciated that the metal selected can have various valence states, forexample, manganese II, III or V can be used. Zinc (II) can also be usedeven though it does not undergo a valence change and therefore will notdirectly scavenge superoxide. The choice of the metal can affectselectivity of the oxygen species that is scavenged. Iron-boundporphines, for example, can be used to scavenge NO.while manganese-boundporphines scavenge NO.less well.

The mimetics of the present invention are of the Formula I:

or pharmaceutically acceptable salt thereofwherein:

R₁ and R₃ are the same and are:

R₂ and R₄ are the same and are:

Y is halogen or —CO₂X,

each X is the same or different and is an alkyl and each R₅ is the sameor different (preferably the same) and is H or alkyl.

Preferably, R₁ and R₃ are the same and are:

R₂ and R₄ are the same and are:

Y is —F or —CO₂X

each X is the same or different and is an alkyl (preferably, C₁₋₄ alkyl,e.g., methyl or ethyl) and each R₅ is the same or different (preferablythe same) and is H or alkyl (preferably, C₁₋₄ alkyl, e.g., —CH₃ or—CH₂CH₃).

Most preferably, R₁, R₂, R₃ and R₄ are the same and are

and each X is the same or different and is C₁₋₄ alkyl, advantageously,methyl or ethyl, particularly, methyl.

Specific examples of mimetics of the invention are shown in FIG. 1,together with activity data.

In addition to the methine (meso) substituents described above, one ormore of the pyrrole rings of the porphyrin of Formula I can besubstituted at any or all beta carbons, ie: 2, 3, 7, 8, 12, 13, 17 or18. Such substituents, designated P, can be hydrogen or an electronwithdrawing group, for example, each P can, independently, be a NO₂group, a halogen (e.g., Cl, Br or F), a nitrile group, a vinyl group, ora formyl group. Such substituents alter the redox potential of theporphyrin and thus enhance its ability to scavenge oxygen radicals. Forexample, there can be 1, 2, 3, 4, 5, 6, 7, or 8 halogen (e.g., Br)substituents (preferably, 1-4), the remaining P's advantageously beinghydrogen. When P is formyl, it is preferred that there not be more than2 (on non-adjacent carbons), more preferably, 1, the remaining P'spreferably being hydrogen. When P is NO₂, it is preferred that there notbe more than 4 (on non-adjacent carbons), more preferably, 1 or 2, theremaining P's being hydrogen.

Where isomers are possible, all such isomers of the herein describedmimetics are within the scope of the invention.

Mimetics preferred for use in the present methods can be selected byassaying for SOD, catalase and/or peroxidase activity. Mimetics can alsobe screened for their ability to inhibit lipid peroxidation or scavengeONOO⁻(as determined by the method of Szabo et al., FEBS Lett. 381:82(1996)).

SOD activity can be monitored in the presence and absence of EDTA usingthe method of McCord and Fridovich (J. Biol. Chem. 244:6049 (1969)). Theefficacy of a mimetic can also be determined by measuring the effect ofthe mimetic on the aerobic growth of a SOD null E. coli strain versus aparent strain. Specifically, parental E. coli (AB1157) and SOD null E.coli. (JI132) can be grown in M9 medium containing 0.2% casamino acidsand 0.2% glucose at pH 7.0 and 37° C.; growth can be monitored in termsof turbidity followed at 700 nm. This assay can be made more selectivefor SOD mimetics by omitting the branched chain, aromatic andsulphur-containing amino acids from the medium (glucose minimal medium(M9), plus 5 essential amino acids).

Efficacy of active mimetics can also be assessed by determining theirability to protect mammalian cells against methylviologen(paraquat)-induced toxicity. Specifically, rat L2 cells grown asdescribed below and seeded into 24 well dishes can be pre-incubated withvarious concentrations of the SOD mimetic and then incubated with aconcentration of methylviologen previously shown to produce an LC₇₅ incontrol L2 cells. Efficacy of the mimetic can be correlated with adecrease in the methylviologen-induced LDH release (St. Clair et al.,FEBS Lett. 293:199 (1991)).

The efficacy of SOD mimetics can be tested in vivo with mouse and/or ratmodels using both aerosol administration and parenteral injection. Forexample, male Balb/c mice can be randomized into 4 groups of 8 mice eachto form a standard 2X2 contingency statistical model. Animals can betreated with either paraquat (40 mg/kg, ip) or saline and treated withSOD mimetic or vehicle control.

Lung injury can be assessed 48 hours after paraquat treatment byanalysis of bronchoalveolar lavage fluid (BALF) damage parameters (LDH,protein and % PMN) as previously described (Hampson et al., Tox. Appl.Pharm. 98:206 (1989); Day et al., J. Pharm. Methods 24:1 (1990)). Lungsfrom 2 mice of each group can be instillation-fixed with 4%paraformaldehyde and processed for histopathology at the lightmicroscopic level.

Catalase activity can be monitored by measuring absorbance at 240 nm inthe presence of hydrogen peroxide (see Beers and Sizer, J. Biol. Chem.195:133 (1952)) or by measuring oxygen evolution with a Clark oxygenelectrode (Del Rio et al., Anal. Biochem. 80:409 (1977)).

Peroxidase activity can be measured spectrophotometrically as previouslydescribed by Putter and Becker: Peroxidases. In: Methods of EnzymaticAnalysis, H. U. Bergmeyer (ed.), Verlag Chemie, Weinheim, pp. 286-292(1983). Aconitase activity can be measured as described by Gardner andFridovich (J. Biol. Chem. 266:19328 (1991)). The selective, reversibleand SOD-sensitive inactivation of aconitase by known O₂ ⁻ generators canbe used as a marker of intracellular O₂ ⁻ generation. Thus, suitablemimetics can be selected by assaying for the ability to protectaconitase activity.

The ability of mimetics to inhibit lipid peroxidation can be assessed asdescribed by Ohkawa et al. (Anal. Biochem. 95:351 (1979)) and Yue et al.(J. Pharmacol. Exp. Ther. 263:92 (1992)). Iron and ascorbate can be usedto initiate lipid peroxidation in tissue homogenates and the formationof thiobarbituric acid reactive species (TBARS) measured.

Active mimetics can be tested for toxicity in mammalian cell culture bymeasuring lactate dehydrogenase (LDH) release. Specifically, rat L2cells (a lung Type II like cell (Kaighn and Douglas, J. Cell Biol.59:160a (1973)) can be grown in Ham's F-12 medium with 10% fetal calfserum supplement at pH 7.4 and 37° C.; cells can be seeded at equaldensities in 24 well culture dishes and grown to approximately 90%confluence; SOD mimetics can be added to the cells at log doses (e.g.,micromolar doses in minimal essential medium (MEM)) and incubated for 24hours. Toxicity can be assessed by morphology and by measuring therelease of the cytosolic injury marker, LDH (e.g., on a thermokineticplate reader), as described by Vassault (In: Methods of EnzymaticAnalysis, Bergmeyer (ed) pp. 118-26 (1983); oxidation of NADH ismeasured at 340 nm).

The mimetics of the present invention are suitable for use in a varietyof methods. The compounds of Formula I, particularly the metal boundforms (advantageously, the manganese bound forms), are characterized bythe ability to inhibit lipid peroxidation. Accordingly, these compoundsare preferred for use in the treatment of diseases or disordersassociated with elevated levels of lipid peroxidation. The compounds arefurther preferred for use in the treatment of diseases or disordersmediated by oxidative stress. Inflammatory diseases are examples,including asthma, inflammatory bowel disease, arthritis and vasculitis.

The compounds of the invention (advantageously, metal bound formsthereof) can also be used in methods designed to regulate NO.levels bytargeting the above-described porphines to strategic locations. NO. isan intercellular signal and, as such, NO. must traverse theextracellular matrix to exert its effects. NO.however, is highlysensitive to inactivation mediated by O₂ ⁻ present in the extracellularspaces. The methine (meso) substituted porphyrins of the invention canincrease bioavalability of NO. by preventing its degradation by O₂ ⁻.

The present invention relates, in a further specific embodiment, to amethod of inhibiting production of superoxide radicals. In thisembodiment, the mimetics of the invention (particularly, metal boundforms thereof) are used to inhibit oxidases, such as xanthine oxidase,that are responsible for production of superoxide radicals. The abilityof a mimetic to protect mammalian cells from xanthine/xanthineoxidase-induced injury can be assessed, for example, by growing rat L2cells in 24-well dishes. Cells can be pre-incubated with variousconcentrations of a mimetic and then xanthine oxidase (XO) can be addedto the culture along with xanthine (X). The appropriate amount of XO/Xused in the study can be pre-determined for each cell line by performinga dose-response curve for injury. X/XO can be used in an amount thatproduces approximately an LC₇₅ in the culture. Efficacy of the mimeticcan be correlated with a decrease in XO/X-induced LDH release.

The mimetics of the invention (particularly, metal bound forms thereof )can also be used as catalytic scavengers of reactive oxygen species toprotect against ischemia reperfusion injuries associated with myocardialinfarction, coronary bypass surgery, stroke, acute head trauma, organreperfusion following transplantation, bowel ischemia, hemorrhagicshock, pulmonary infarction, surgical occlusion of blood flow, and softtissue injury. The mimetics (particularly, metal bound forms) canfurther be used to protect against skeletal muscle reperfusion injuries.The mimetics (particularly, metal bound forms) can also be used toprotect against damage to the eye due to sunlight (and to the skin) aswell as glaucoma, cataract and macular degeneration of the eye. Themimetics (particularly, metal bound forms) can also be used to treatbums and skin diseases, such as dermatitis, psoriasis and otherinflammatory skin diseases. Diseases of the bone are also amenable totreatment with the mimetics. Further, connective tissue disordersassociated with defects in collagen synthesis or degradation can beexpected to be susceptible to treatment with the present mimetics(particularly, metal bound forms), as should the generalized deficits ofaging. Liver cirrhosis and renal diseases (including glomerulanephritis, acute tabular necrosis, nephroderosis and dialysis inducedcomplications) are also amenable to treatment with the present mimetics(particularly, metal bond forms thereof).

The mimetics of the invention (particularly, metal bound forms) can alsobe used as catalytic scavengers of reactive oxygen species to increasethe very limited storage viability of transplanted hearts, livers,lungs, kidneys, skin and other organs and tissues. The invention alsoprovides methods of inhibiting damage due to autoxidation of substancesresulting in the formation of O₂ ⁻ including food products,pharmaceuticals, stored blood, etc. To effect this end, the mimetics ofthe invention are added to food products, pharmaceuticals, stored bloodand the like, in an amount sufficient to inhibit or prevent oxidationdamage and thereby to inhibit or prevent the degradation associated withthe autoxidation reactions. (For other uses of the mimetics of theinvention, see U.S. Pat. 5,227,405). The amount of mimetic to be used ina particular treatment or to be associated with a particular substancecan be determined by one skilled in the art.

The mimetics (particularly, metal bound forms) of the invention canfurther be used to scavenge hydrogen peroxide and thus protect againstformation of the highly reactive hydroxyl radical by interfering withFenton chemistry (Aruoma and Halliwell, Biochem. J. 241:273 (1987);Mello Filho et al., Biochem. J. 218:273 (1984); Rush and Bielski, J.Phys. Chem. 89:5062 (1985)). The mimetics (particularly, metal boundforms) of the invention can also be used to scavenge peroxynitrite, asdemonstrated indirectly by inhibition of the oxidation ofdihydrorhodamine 123 to rhodamine 123 and directly by acceleratingperoxynitrite degradation by stop flow analysis.

Further examples of specific diseases/disorders appropriate fortreatment using the mimetics of the present invention, advantageously,metal bound forms, include diseases of the cardiovascular system(including cardiomyopathy, ischemia and atherosclerotic coronaryvascular disease), central nervous system (including AIDS dementia,stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease andHuntington's disease) and diseases of the musculature (includingdiaphramic diseases (e.g., respiratory fatigue in chronic obstructivepulmonary disease, cardiac fatigue of congestive heart failure, muscleweakness syndromes associated with myopathies, ALS and multiplesclerosis). Many neurologic disorders (including epilepsy, stroke,Huntington's disease, Parkinson's disease, ALS, Alzheimer's and AIDSdementia) are associated with an over stimulation of the major subtypeof glutamate receptor, the NMDA (or N-methyl-D-aspartate) subtype. Onstimulation of the NMDA receptor, excessive neuronal calciumconcentrations contribute to a series of membrane and cytoplasmic eventsleading to production of oxygen free radicals and nitric oxide (NO.).Interactions between oxygen free radicals and NO.have been shown tocontribute to neuronal cell death. Well-established neuronal corticalculture models of NMDA-toxicity have been developed and used as thebasis for drug development. In these same systems, the mimetics of thepresent invention inhibit NMDA induced injury. The formation of O₂ ⁻radicals is an obligate step in the intracellular events culminating inexcitotoxic death of cortical neurons and further demonstrate that themimetics of the invention can be used to scavenge O₂ ⁻ radicals andthereby serve as protectants against excitotoxic injury.

The present invention also relates to methods of treating AIDS. The NfKappa B promoter is used by the HIV virus for replication. This promoteris redox sensitive, therefore, an oxidant can regulate this process.This has been shown previously for two metalloporphyrins distinct fromthose of the present invention (Song et al., Antiviral Chem. andChemother. 8:85 (1997)). The invention also relates to methods oftreating systemic hypertension, atherosclerosis, edema, septic shock,pulmonary hypertension, including primary pulmonary hypertension,impotence, infertility, endometriosis, premature uterine contractions,microbial infections, gout and in the treatment of Type I or Type IIdiabetes mellitus. The mimetics of the invention (particularly, metalbound forms) can be used to ameliorate the toxic effects associated withendotoxin, for example, by preserving vascular tone and preventingmulti-organ system damage.

As indicated above, inflammations, particularly inflammations of thelung, are amenable to treatment using the present mimetics(particularly, metal bound forms) (particularly the inflammatory baseddisorders of emphysema, asthma, ARDS including oxygen toxicity,pneumonia (especially AIDS-related pneumonia), cystic fibrosis, chronicsinusitis, arthritis and autoimmune diseases (such as lupus orrheumatoid arthritis)). Pulmonary fibrosis and inflammatory reactions ofmuscles, tendons and ligaments can be treated using the present mimetics(particularly metal bound forms thereof). EC—SOD is localized in theinterstitial spaces surrounding airways and vasculature smooth musclecells. EC—SOD and O₂ ⁻ mediate the antiinflammatory-proinflammatorybalance in the alveolar septum. NO.released by alveolar septal cellsacts to suppress inflammation unless it reacts with O₂ ⁻ to form ONOO—.By scavenging O₂ ⁻, EC—SOD tips the balance in the alveolar septumagainst inflammation. Significant amounts of ONOO— will form only whenEC—SOD is deficient or when there is greatly increased O₂ ⁻ release.Mimetics described herein can be used to protect against destructioncaused by hyperoxia.

The invention further relates to methods of treating memory disorders.It is believed that nitric oxide is a neurotransmitter involved inlong-term memory potentiation. Using an EC—SOD knocked-out mouse model(Carlsson et al., Proc. Natl. Acad. Sci. USA 92:6264 (1995)), it can beshown that learning impairment correlates with reduced superoxidescavenging in extracellular spaces of the brain. Reduced scavengingresults in higher extracellular O₂ ⁻ levels. O₂ ⁻ is believed to reactwith nitric oxide thereby preventing or inhibiting nitric oxide-mediatedneurotransmission and thus long-term memory potentiation. The mimeticsof the invention, particularly, metal bound forms, can be used to treatdementias and memory/learning disorders.

The availability of the mimetics of the invention also makes possiblestudies of processes mediated by O₂ ⁻, hydrogen peroxide, nitric oxideand peroxynitrite.

The mimetics described above, metal bound and metal free forms, can beformulated into pharmaceutical compositions suitable for use in thepresent methods. Such compositions include the active agent (mimetic)together with a pharmaceutically acceptable carrier, excipient ordiluent. The composition can be present in dosage unit form for example,tablets, capsules or suppositories. The composition can also be in theform of a sterile solution suitable for injection or nebulization.Compositions can also be in a form suitable for opthalmic use. Theinvention also includes compositions formulated for topicaladministration, such compositions taking the form, for example, of alotion, cream, gel or ointment. The concentration of active agent to beincluded in the composition can be selected based on the nature of theagent, the dosage regimen and the result sought.

The dosage of the composition of the invention to be administered can bedetermined without undue experimentation and will be dependent uponvarious factors including the nature of the active agent (includingwhether metal bound or metal free), the route of administration, thepatient, and the result sought to be achieved. A suitable dosage ofmimetic to be administered IV or topically can be expected to be in therange of about 0.01 to 50 mg/kg/day, preferably, 0.1 to 10 mg/kg/day.For aerosol administration, it is expected that doses will be in therange of 0.001 to 5.0 mg/kg/day, preferably, 0.01 to 1 mg/kg/day.Suitable doses of mimetics will vary, for example, with the mimetic andwith the result sought.

Certain aspects of the present invention will be described in greaterdetail in the non-limiting Examples that follow. (The numbering of thecompounds in Example I is for purposes of that Example only.)

EXAMPLE I Syntheses I.[5,15-Bis(4-carbomethoxyphenyl)-10,20-(thiazol-5-yl)porphyrinato]-manganese(III) Chloride (5).

1. meso-(Thiazol-5-yl)dipyrromethane (2).

In a foil-covered 250-mL three-necked flask, equipped with a magneticstirrer and N₂ inlet, was placed 5-thiazolecarboxaldehyde (1, 0.88 g,7.81 mmol) (Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini,P. Synthesis 1987, 998-1001), CH₂Cl₂ (30 mL), and pyrrole (6 mL, 87mmol). The reaction mixture was stirred for 10 min, then TFA (0.25 mL,3.2 mmol) was added. After a stirring period of 2 h at room temperature,the reaction mixture was transferred to a separatory funnel and washedwith saturated aqueous NaHCO₃ (50 mL), H₂O (50 mL) and brine (50 mL).The organic layer was dried (Na₂SO₄), filtered, and concentrated invacuo. The residue was dissolved in CH₂Cl₂ (50 mL) and adsorbed ontosilica gel (3 g). Purification by column chromatography (gradientelution 33-67% EtOAc/hexanes) provided dipyrromethane 2 (0.95 g, 52%) asa gray solid: ¹H NMR (300 MHz, CDCl₃) δ 5.74 (s, 1 H), 6.02 (m, 2 H),6.17 (m, 2 H), 6.70 (m, 2 H), 7.58 (s, 1 H), 8.19 (br s, 2 H), 8.68 (s,1 H).

2. 5,15-Bis(4-carbomethoxyphenyl)-10,20-(thiazol-5-yl)porphyrin (4).

In a foil-covered 250-mL three-necked round bottom flask, equipped witha magnetic stirrer and a N₂ outlet, was added methyl 4-formylbenzoate(3, 180 mg, 1.09 mmol), dipyrromethane 2 (249 mg, 1.09 mmol), and CH₂Cl₂(110 mL). The reaction mixture was stirred for 15 min, then TFA (0.25mL, 3.25 mmol) was added. After a stirring period of 2.5 h at roomtemperature, DDQ (372 mg, 1.64 mmol) was added. The reaction mixture wasstirred overnight and the solvent was removed in vacuo. The cruderesidue was adsorbed onto silica gel (3 g) then purified by columnchromatography (gradient elution 0- 1.5% MeOH/CH₂Cl₂) to provideporphyrin 4 (80 mg, 10% yield) as a purple solid: ¹H NMR (300 MHz,CDCl₃) δ −2.75 (s, 2 H), 4.11 (s, 6 H), 8.28 (d, 4 H), 8.47 (d, 4 H),8.65 (s, 2 H), 8.82 (d, 4 H), 8.99 (d, 4 H), 9.33 (s, 2 H).

3.[5,15-Bis(4-carbomethoxyphenyl)-10,20-(thiazol-5-yl)porphyrinato]-manganese(III) Chloride (5).

A solution of porphyrin 4 (75 mg, 0.101 mmol) and MnCl₂ (129 mg, 1.03mmol) in DMF (15 mL) was heated at 125° C. for 14.5 h. The mixture wascooled to room temperature while exposed to a stream of air, thenconcentrated in vacuo. Repeated chromatographic purification of theproduct (gradient elution 5-10% MeOH/CH₂Cl₂) provided porphryin 5 (7 mg,8%) as a dark green solid: mp>300° C.; UV-vis λ_(max)=466.0 nm,ε=1.34×10⁵ L/cm-mol; API MS m/z=797 [C₄₂H₂₆MnN₆O₄S₂]⁺.

II. [5,10,15,20-Tetrakis(thiazol-5-yl)porphyrinato]manganese (III)Chloride (7) and[5,10,15,20-Tetrakis(3-methylthiazolium-5-yl)porphyrinato]manganese(III) Pentachloride (9).

1. 5,10,15,20-Tetrakis(thiazol-5-yl)porphyrin (6).

A 250-mL three-necked flask equipped with a condenser and charged withpropionic acid (60 mL) was heated to reflux. 5-Thiazolecarboxaldehyde(1, 373 mg, 3.30 mmol), pyrrole (230 μL, 3.32 mmol), and an additional 5mL of propionic acid were added. After 3.5 h at reflux, the mixture wascooled to room temperature while exposed to a stream of air. The solventwas removed in vacuo, the residue was redissolved inCHCl₃/MeOH/concentrated NH₄OH (6:3:1; 100 mL), and the solvent wasremoved in vacuo. The residue was adsorbed onto silica gel (3 g) andpurified by column chromatography (gradient elution, 1-2% MeOH/CH₂Cl₂)to provide porphyrin 6 (123 mg, 14%) as a solid: ¹H NMR (300 MHz, CDCl₃)δ −2.70 (s, 2 H), 8.67 (s, 4 H), 9.02 (s, 8 H), 9.38 (s, 4 H).

2. [5,10,15,20-Tetrakis(thiazol-5-yl)porphyrinato]manganese (III)Chloride (7).

A solution of porphyrin 6 (61 mg, 0.115 mmol) and MnCl₂ (144 mg, 1.14mmol) in DMF (15 mL) was heated at 125° C. for 7.5 h. A stream of airwas introduced and the reaction mixture was warmed to 130° C. After astirring period of 1.5 h, the reaction mixture was cooled to roomtemperature. The solvent was evaporated in vacuo, and the residue wasadsorbed onto silica gel (2 g). Purification by column chromatography(gradient elution, 10-20% MeOH/CH₂Cl₂) provided porphyrin 7 (36 mg, 43%)as a dark green solid: mp >300° C.; UV-vis λ_(max)=466.5 nm, ε=3.55×10⁴L/cm-mol; FAB MS m/z=695 [C₃₂H₁₆MnN₈S₄]⁺.

3. 5,10,15,20-Tetrakis(3-methylthiazolium-5-yl)porphyrin Tetrachloride(8).

A solution of 6 (123 mg, 0.19 mmol), CH₃I (5 mL), and DMF (5 mL) in asealed tube was heated at 100° C. for 24 h. The crude porphyrin iodidesalt that precipitated out of the reaction mixture was filtered, washedalternately with CH₂Cl₂ and ether, and dried under vacuum at roomtemperature. The iodide was dissolved in water, precipitated out as thehexafluorophosphate salt (by dropwise addition of aqueous NH₄ ⁺PF₆ ⁻solution; 1 g/10 mL), filtered, washed with water and isopropanol, andvacuum dried at room temperature. The hexafluorophosphate salt wasdissolved in acetone then filtered (to remove insoluble solids). Theproduct was precipitated out as the chloride salt from the filtrate bydropwise addition of a solution of Bu₄NH₄ ⁺Cl⁻ in acetone (1 g/10 mL),filtered, washed with copious quantities of acetone, and dried undervacuum at room temperature, to provide porphyrin 8 (66 mg, 41%): ¹H NMR(300 MHz, DMSO-d₆) −3.1 (s, 2 H), 4.6 (s, 12 H), 9.49 (s, 4 H), 9.58 (s,8 H), 10.85 (s, 4 H).

4. [5,10,15,20-Tetrakis(3-methylthiazolium-5-yl)porphyrinato]manganese(III) Pentachloride (9).

Porphyrin 8 (60 mg, mmol) was dissolved in water (15 mL) and thesolution pH was adjusted to pH=12 by dropwise addition of 6N NaOH. SolidMnCl₂ (147 mg) was added into the reaction mixture (the resultingpH=8.7). After a stirring period of 30-60 min, the reaction mixture wasfiltered through a fritted funnel lined with a filter paper. The pH ofthe filtrate was adjusted to pH=4-5 (1N HCl) then the solution wasfiltered. Purification by the double precipitation method (as describedfor the preparation of 8) provided porphyrin 9

(6 mg, 8.2%) as a dark brown solid: mp>300° C.; UV-vis λ_(max)=460.0 nm,ε=1.25×10⁵ L/cm-mol.

III. [5,15-Bis(thiazol-5-yl)porphyrinato]manganese (III) Chloride (12).

1. 5,15-Bis(thiazol-5-yl)porphyrin (11).

In a foil-covered 500-mL three-necked round bottom flask, equipped withmagnetic stirrer and a N₂ inlet, was added dipyrromethane 10 (288 mg,1.97 mmol) (Chong, R.; Clezy, P. S.; Liepa, A. J.; Nichol, A. W. Aust.J. Chem. 1969, 22, 229), 5-thiazolecarboxaldehyde (1, 223 mg, 1.97mmol), CH₂Cl₂ (198 mL) and sodium chloride (13 mg, 0.2 mmol). Thereaction mixture was stirred vigorously for 10 min, then TFA (0.46 mL,5.97 mmol) was added. After a stirring period of 40 min, DDQ (671 mg,2.96 mmol) was added, and the reaction mixture was stirred for anadditional 4 h. The solvent was evaporated in vacuo, and the residue wasadsorbed onto silica gel (3 g). Repeated chromatographic purification(gradient elution 0.5-2% MeOH/CH₂C₂) provided porphyrin 11 (28 mg, 6%)as a solid: ¹H NMR (300 MHz, CDCl₃) δ −3.07 (s, 2 H), 8.69 (s, 2 H),9.21 (d, 4 H), 9.39 (s, 2 H), 9.43 (d, 4 H), 10.35 (s, 2 H).

2. [5,15-Bis(thiazol-5-yl)porphyrinato]manganese (III) Chloride (12).

A solution of porphyrin 11 (28 mg, 0.0587 mmol) and MnCl₂ (85 mg, 0.675mmol) in DMF (8 mL) was heated at 125° C. for 15 h. The mixture wascooled to room temperature while exposed to a stream of air, and thesolvent was removed by rotary evaporation. The residue was dissolved in10% MeOH/CH₂CI₂ (50 mL) and adsorbed onto silica gel (500 mg).Purification by column chromatography (gradient of 5-10% MeOH/CH₂Cl₂)provided porphyrin 12 (29 mg, 86%) as a dark brown solid: mp>300° C.;UV-vis λ_(max)=457.5 nm, ε=3.75×10⁴ L/cm-mol; API MS m/z=529[C₂₆H₁₄MnN₆S₂]⁺.

IV.[5,15-Bis(4-carbomethoxyphenyl)-10,20-bis(3-methylthiazolium-2-yl)porphyrinato]manganese(III) Trichloride (16).

1. meso-(Thiazol-2-yl)dipyrromethane (14).

In a foil-covered 250-mL three-necked flask, equipped with a magneticstirrer and a N₂ inlet, was placed 2-thiazolecarboxaldehyde (13, 0.97 g,8.6 mmol) (Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini,P. Synthesis 1987, 998-1001), CH₂Cl₂ (35 mL), and pyrrole (7.2 mL, 104mmol). The reaction mixture was stirred for 10 min, then TFA (0.26 mL,3.4 mmol) was added. After a stirring period of 1 h at room temperature,the reaction mixture was transferred to a separatory funnel and washedwith saturated aqueous NaHCO₃ (50 mL), H₂O (50 mL), and brine (50 mL).The organic layer was dried (Na₂SO₄), filtered, and concentrated invacuo. The residue was dissolved in CH₂Cl₂ (50 mL), and adsorbed ontosilica gel (3 g). Purification by column chromatography (1:1ether/hexanes) provided dipyrromethane 14 (1.22 g, 62%) as a solid: ¹HNMR (300 MHz, CDCl₃) δ 5.78 (s, 1 H), 6.04 (s, 2 H), 6.15 (m, 2 H), 6.71(m, 2 H), 7.20 (d, 1 H), 7.74 (d, 1 H), 8.81 (br s, 1 H).

2. 5,15-Bis(4-carbomethoxyphenyl)-10,20-(thiazol-2-yl)porphyrin (15).

In a foil-covered 500-mL three-necked round bottom flask, equipped witha magnetic stirrer and a N₂ outlet, was added dipyrromethane 14 (771 mg,3.39 mmol), methyl 4-formylbenzoate (3, 0.557 g, 3.36 mmol) and CH₂Cl₂(350 mL). The reaction mixture was stirred for 15 min, then TFA (0.8 mL,10.4 mmol) was added. After a stirring period of 3 h at roomtemperature, DDQ (1.16 g, 1.64 mmol) was added. The reaction mixture wasstirred for 2 d, then the solvent was removed in vacuo. The residue wasadsorbed onto silica gel (4 g) and purified by column chromatography(gradient elution 0.5-1% MeOH/CH₂Cl₂) to provide porphyrin 15 (140 mg,11%) as a purple solid: (300 MHz, CDCl₃) δ −2.29 (s, 2 H), 4.12 (s, 6H), 8.02 (d, 2 H), 8.30 (d, 4 H), 8.44 (d, 2 H), 8.47 (d, 4 H), 8.84 (d,4 H), 9.05 (d, 4 H).

3.[5,15-Bis(4-carbomethoxyphenyl)-10,20-bis(3-methylthiazolium-2-yl)-porphyrinato]manganese(III) Trichloride (16).

A solution of porphyrin 15 (26 mg, 0.054 mmol) and MnCl₂ (40 mg, 0.40mmol) in DMF (20 mL) was heated at 135° C. overnight. The mixture wascooled to 45° C. and CH₃I (0.8 mL, 11.2 mmol) was added. The reactionmixture was stirred for 36 h at 45° C. and DMF was evaporated in vacuo.The residue was purified by column chromatography (gradient elutionEtOAc, CHCl₃, MeOH, concentrated NH₄OH) to provide the productcontaminated with impurities. Following a second purification by columnchromatography (6:3:1 CHCl₃/MeOH/concentrated NH₄OH) non-polar fractionswere collected leaving the bulk of product at the top of the column. Thetop silica gel containing the product was collected and washed withCHCl₃/MeOH/1N HCl (6:4:1). Evaporation of the acidic solution providedthe product that contained excess inorganic salts. Purification by thedouble precipitation method and vacuum drying at 35° C. for 2 d providedporphyrin 16 (9 mg, 28%) as a black solid: mp>300° C.; UV-visλ_(max)=459.0 nm; ε=1.36×10⁵ L/cm-mol; API MS m/z=886[C₄₄H₃₂MnN₆O₄S₂+CH₃CO₂ ⁻]⁺².

V. [5,15-Bis(3-methylthiazolium-2-yl)porphyrinato]manganese (III)Trichloride (19).

1. 5,15-Bis(thiazol-2-yl)porphyrin (17).

In a foil-covered 500-mL three-necked round bottom flask, equipped withmagnetic stirrer and a N₂ inlet, was added dipyrromethane (10, 677 mg,4.6 mmol), 2-thiazol-carboxaldehyde (13, 524 mg, 4.6 mmol), and CH₂Cl₂(450 mL). The reaction mixture was stirred for 10 min, then TFA (1 mL,16.9 mmol) was added. After a stirring period of 1 h, DDQ (1.58 g, 7mmol) was added and the reaction mixture was stirred overnight. Thesolvent was evaporated in vacuo, and the residue was adsorbed ontosilica gel (3 g). Repeated purification by column chromatography(gradient elution 1-2% MeOH/CH₂Cl₂) provided porphyrin 17 (51 mg, 4.62%)as a purple solid: ¹H NMR (300 MHz, CDCl₃) δ −3.05 (s, 2 H), 8.06 (d, 2H), 8.51 (d, 2 H), 9.35 (d, 4 H), 9.45 (d, 4 H), 10.40 (s, 2 H).

2. 5,15-Bis(3-methylthiazolium-2-yl)porphyrin Dichloride (18).

A solution of porphyrin 17 (140 mg, 0.29 mmol), CH₃I (4 mL), and DMF (20mL) in a sealed tube was heated at 100° C. for 48 h. The precipitatethat formed during the reaction was filtered and washed with ether.Purification of the solid precipitate by the double precipitation methodprovided porphyrin 18 (120 mg, 71%) as a purple solid: ¹H NMR (300 MHz,DMSO-d₆) δ −3.4 (s, 2 H), 4.09, 4.06 (2 s, 6 H, atropisomer N—CH₃), 9.07(d, 2 H), 9.2 (d, 2 H), 9.4 (d, 4 H), 9.9 (d, 4 H), 10.96 (s, 2 H).

3. [5,15-Bis(3-methylthiazolium-2-yl)porphyrinato]manganese (III)Trichloride (19).

Porphyrin 18 (120 mg, 0.21 mmol) was dissolved in water (25 mL) and thesolution pH was adjusted to pH=12 by dropwise addition of 6N NaOH. SolidMnCl₂ (147 mg) was added (the resulting pH=8.7) and the reaction mixturewas stirred for 30-60 min. The reaction mixture was filtered through afritted funnel lined with a filter paper. The pH of the filtrate wasadjusted to pH=4-5 (1N HCl) and the solution was filtered. The filtratewas subjected to the double precipitation method to provide a mixture ofporphyrins 18 and 19. The resulting mixture was separated by columnchromatography (9:0.5:0.5 CH₃CN/water/saturated KNO₃) to provideporphyrin 19 (25 mg, 18%) as a dark solid: mp>300° C.; UV-visλ_(max)=450.5 nm, ε=5.99×10⁴ L/cm-mol.

VI. [5,10,15,20-Tetrakis(1-methylimidazol-2-yl)porphyrinato]manganese(III) Chloride (22) and[5,10,15,20-Tetrakis(1,3-dimethylimidazolium-2-yl)-porphyrinato]manganese(III) Pentachloride (24)

1. 5,10,15,20-Tetrakis(1-methylimidazol-2-yl)porphyrin (21).

In a foil-covered 1-L three-neck flask equipped with magnetic stirrer,thermometer, and condenser was placed aldehyde 20 (2.0 g, 18.2 mmol) andpropionic acid (400 mL). The reaction mixture was heated to 120° C. atwhich time pyrrole (1.26 mL, 18.2 mmol) was added. The reaction mixturewas heated under reflux for an additional 4.5 h and was stirred at roomtemperature for 3 d. The propionic acid was removed in vacuo, the darkresidue was dissolved in a solution of 5% MeOH/CH₂Cl₂ and adsorbed ontosilica gel (18 g). Repeated column chromatographic purification providedporphyrin 21 (280 mg, 10%) as a purple solid: ¹H NMR (300 MHz, CDCl₃) δ−2.94, −2.90, −2.84 (3 s, 2 H, atropisomer NH), 3.39-3.58 (multiple s,12 H, atropisomer N—CH₃), 7.50 (d, 4 H), 7.71 (d,4 H),8.92 (m,8 H).

2. [5,10,15,20-Tetrakis(1-methylimidazol-2-yl)porphyrinato]manganese(III) Chloride (22).

A solution of porphyrin 21 (29.9 mg, 0.047 mmol) and MnCl₂ (61 mg, 0.48mmol) in DMF (12 mL) was heated at 120° C. for 14 h. The mixture wascooled to room temperature while exposed to a stream of air, andconcentrated by rotary evaporation. Purification by columnchromatography (CHCl₃/MeOH/concentrated NH₄OH/EtOAc) provided porphyrin22 (12.5 mg, 37%) as a black solid: mp>300° C.; UV-vis λ_(max)=463.0 nm;ε=9.35×104 L/cm-mol; API MS m/z=683 [C₃₆H₂₈MnN₁₂]⁺.

3. 5,10,15,20-Tetrakis(1,3-dimethylimidazolium-2-yl)porphyrinTetrachloride (23).

A solution of porphyrin 21 (589 mg, 0.934 mmol) and CH₃I (3 mL, 48 mmol)in DMF (10 mL) was heated in a sealed tube at 100° C. for 14 h. Thereaction mixture was poured into ethyl acetate (200 mL) causingporphyrin 23 to precipitate as the iodide salt. The solution wasfiltered and the brown solid was washed with EtOAc and ether. Theproduct was purified by column chromatography (CH₃CN/water/saturatedKNO₃) and subjected to the double precipitation method to provideporphyrin 23 (540 mg, 69%) as a purple solid: ¹H NMR (300 MHz, DMSO-d₆)δ −3.22 (s, 2 H), 3.78 (s, 24 H), 8.60 (s, 8 H), 9.44 (s, 8 H).

4.[5,10,15,20-Tetrakis(1,3-dimethylimidazolium-2-yl)porphyrinato]manganese(III) Pentachloride (24).

Porphyrin 23 (1.0 g, 0.83 mmol) was dissolved in MeOH (550 mL) thenMnCl₂ (1.57 g, 12.5 mmol) was added. The solution pH was adjusted topH=7.3 with 6N NaOH while bubbling a stream of air into the reactionmixture. The pH of the solution was maintained pH>7.3 for 1 h thenadjusted to pH=4.5 with 1N HCI. The solution was filtered and theprecipitate subjected to the double precipitation method and dried toprovide porphyrin 24 (0.570 g, 74%) as a solid: mp>300° C.; UV-visλ_(max)=460.5 nm; ε=8.38×10⁴ L/cm-mol; FAB MS m/z=778 [C₄₀H₄₀MnN₁₂]⁺⁴.

VII.[5,15-Bis(4-carbomethoxyphenyl)-10,20-bis(1-methylimidazol-2-yl)-porphyrinato]manganese(III) Chloride (27) and[5,15-Bis(4-carbomethoxy-phenyl)-10,20-bis(1,3-dimethylimidazolium-2-yl)porphyrinato]manganese(III) Trichloride (29).

1.5,15-Bis(4-carbomethoxyphenyl)-10,20-bis(1-methylimidazol-2-yl)porphyrin(26).

In a foil-covered 500-mL three-necked flask, equipped with a magneticstirrer and N₂ inlet, was placed dipyrromethane 25 (0.71 g, 3.09 mmol),CH₂Cl₂ (310 mL), aldehyde 4 (50 mg, 3.09 mmol), and NaCl (22.4 mg, 0.35mmol). The reaction mixture was stirred for 10 min, then TFA (1.48 mL,19.2 mmol) was added. After a stirring period of 4 h at roomtemperature, DDQ (1.05 g, 4.65 mmol) was added. The reaction mixture wasstirred overnight and the solvent was removed in vacuo. The residue wasadsorbed onto silica gel (10 g) then purified by column chromatography(gradient elution 2-4% EtOAc/hexanes) to provide porphyrin 26 (220 g,24%) as a purple solid: ¹H NMR (300 MHz, CDCl₃) δ −2.85 (s, 2 H), 3.43,3.49 (2 s, 6 H, atropisomer N—CH₃), 4.14 (s, 6 H), 7.49 (d, 2 H), 7.68(d, 2 H), 8.30 (d, 4 H), 8.48 (d, 4 H), 8.87 (m, 8 H).

2.[5,15-Bis(4-carbomethoxyphenyl)-10,20-bis(1-methylimidazol-2-yl)-porphyrinato]manganese(III) Chloride (27).

A solution of porphyrin 26 (50.7 mg, 0.071 mmol) and MnCl₂ (88.6 mg,0.70 mmol) in DMF (20 mL) was heated at 120° C. for 14 h. The mixturewas cooled to room temperature while exposed to a stream of air, thenconcentrated by rotary evaporation. Purification by columnchromatography (gradient elution 5-10% MeOH/CH₂Cl₂) provided porphyrin27 (25 mg, 42%) as a black solid: mp>300° C.; UV-vis λ_(max)=463.0 nm;ε=6.70×10⁴ L/cm-mol; FAB MS m/z=791 [C₄₄H₃₂MnN₈O₄]⁺.

3.5,15-Bis(4-carbomethoxyphenyl)-10,20-bis(1,3-dimethylimidazolium-2-yl)-porphyrinDichloride (28).

A solution of porphyrin 26 (80 mg, 0.11 mmol), DMF (7 mL) and CH₃I(0.150 mL) was stirred at room temperature for 4 h. The solvent wasremoved by rotary evaporation to give a dark colored residue. Theresidue was purified by column chromatography (CHCl₃/MeOH/concentratedNH₄OH/EtOAc) to provide porphyrin 28 (21 mg, 18%) as a purple solid: ¹HNMR (300 MHz, DMSO-d₆) δ −3.02 (s, 2 H), 3.73 (s, 12 H), 4.08 (s, 6 H),8.45 (q, 8 H), 8.56 (s, 4 H), 9.13 (s, 8 H); API MS m/z=384[C₄₆H₄₀MnN₈O₄]⁺².

4.[5,15-Bis(4-carbomethoxyphenyl)-10,20-bis(1,3-dimethylimidazolium-2-yl)-porphyrinato]manganese(III) Trichloride (29).

A solution of porphyrin 28 (19.5 mg, 0.022 mmol) and MnCl₂ (22.4 mg,0.18 mmol) in DMF (5 mL) was heated at 120° C. for 14 h. The reactionmixture was cooled to room temperature while exposed to a stream of air,then concentrated by rotary evaporation. Purification by columnchromatography (CHCl₃/MeOH/concentrated NH₄OH/EtOAc) provided crudeporphyrin 28. Purification by the double precipitation method and dryingprovided porphyrin 29 (6.5 mg, 37%) as a solid: mp>300° C.; UV-visλ_(max)=447.5 nm; ε=1.27×10⁵ L/cm-mol; FAB MS m/z=856 [C₄₆H₃₈MnN₈O₄]⁺².

VIII.[5,15-Bis(carboethoxy)-10,20-bis(1-methylimidazol-2-yl)porphyrinato]-manganese(III) Chloride (32).

1. 5,15-Bis(carboethoxy)-10,20-bis(1-methylimidazol-2-yl)porphyrin (31).

In a foil-covered 500-mL three-necked flask, equipped with a magneticstirrer and N₂ inlet, was placed dipyrromethane 25 (0.5 g, 2.2 mmol),CH₂Cl₂ (220 mL), and aldehyde 30 (225 mg, 2.2 mmol). The reactionmixture was stirred for 10 min, then TFA (1.0 mL, 12.9 mmol) was added.After a stirring period of 2 h at room temperature, DDQ (750 mg, 3.3mmol) was added, and the reaction mixture was stirred overnight.Triethylamine (2.0 mL) was added, the solvent was evaporated in vacuo,and the residue adsorbed onto silica gel (10 g). Purification by columnchromatography (5% EtOH/CHCl₃) provided porphyrin 31 (86 mg, 13%) as apurple solid: ¹H NMR (300 MHz, CDCl₃) δ −3.08, −3.06 (2 s, 2 H,atropisomer NH), 1.82 (t, 6 H), 3.40, 3.49 (2 s, 6 H, atropisomerN—CH₃), 5.11 (q, 4 H), 7.53 (d, 2 H), 7.72 (d, 2 H), 8.94 (m, 4 H), 9.50(d, 4 H).

2.[5,15-Bis(carboethoxy)-10,20-bis(1-methylimidazol-2-yl)porphyrinato]-manganese(III) Chloride (32).

A solution of porphyrin 31 (27.7 mg, 0.045 mmol) and MnCl₂ (59.1 mg,0.47 mmol) in DMF (12.5 mL) was heated at 120° C. for 14 h. AdditionalMnCl₂ (29 mg, 0.23 mmol) was added and the reaction mixture was heatedfor another 2 h. The reaction mixture was cooled to room temperaturewhile exposed to a stream of air, then concentrated by rotaryevaporation. Air was bubbled into a solution of the product dissolved inethanol with two drops of 1N HCl. The solvent was evaporated in vacuo togive a dark colored residue. Purification by column chromatography(gradient elution 10-30% EtOH/CHCl₃) provided porphyrin 32 (6.5 mg, 35%)as a black solid: mp>300° C.; UV-vis λ_(max)=458.5 nm; ε=6.01×10⁴L/cm-mol; API MS m/z=667 [C₃₄H₂₈MnN₈O₄]⁺.

IX. [5,15-Bis(1-methylimidazol-2-yl)porphyrinato]manganese (III)Chloride (34) and[5,15-Bis(1,3-dimethylimidazolium-2-yl)porphyrinato]manganese (III)Trichloride (36).

1. 5,15-Bis(1-methylimidazol-2-yl)porphyrin (33).

In a foil-covered 1-L three-necked flask, equipped with a magneticstirrer and N₂ inlet, was placed dipyrromethane 10 (1.0 g, 6.84 mmol),CH₂Cl₂ (680 mL), and aldehyde 20 (753 mg, 6.84 mmol). The reactionmixture was stirred for 10 min, then TFA (3.1 mL, 40.2 mmol) was added.After a stirring period of 2 h at room temperature, DDQ (2.3 g, 10.1mmol) was added and the reaction mixture was stirred overnight.Triethylamine (5.75 mL) was added into the reaction mixture, the solventwas evaporated in vacuo and the residue was adsorbed onto silica gel (15g). Purification by column chromatography (6% MeOH/CH₂Cl₂) providedporphyrin 33 (0.120 g, 7%) as a purple solid: ¹H NMR (300 MHz, CDCl₃) δ−3.28 (s, 2 H), 3.45, 3.52 (2 s, 6 H, atropisomer N—CH₃), 7.53 (d, 2 H),7.74 (d, 2 H), 9.07 (m, 4 H), 9.46 (d, 4 H), 10.37 (s, 2 H).

2. [5,15-Bis(1-methylimidazol-2-yl)porphyrinato]manganese (III) Chloride(34).

A solution of porphyrin 33 (50 mg, 0.106 mmol) and MnCl₂ (180 mg, 1.4mmol) in DMF (20 mL) was heated at 120° C. for 14 h. The mixture wascooled to room temperature while exposed to a stream of air, thenconcentrated by rotary evaporation. Purification by columnchromatography (33% MeOH/CHCl₃) provided porphyrin 34 (32 mg, 53%) as ablack solid: mp>300° C.; UV-vis λ_(max)=454.5 nm; ε=4.98×10⁴ L/cm-mol;API MS m/z=523 [C₂₈H₂₀MnN₈]⁺.

3. 5,15-Bis(1,3-dimethylimidazolium-2-yl)porphyrin Dichloride (35).

Porphyrin 33 (95 mg, 0.20 mmol) was dissolved in DMF (15 mL), CH₃I (0.5mL, 8.03 mmol) was added, and the reaction mixture stirred for 48 h. TheDMF was evaporated in vacuo and the dark colored residue was purified bycolumn chromatography (gradient elution 30% MeOH/CH₂Cl₂ to 6:4:1CHCl₃/MeOH/1N HCl) to provide porphyrin 35 (150 mg, 99%) as a purplesolid: ¹H NMR (300 MHz, DMSO-d₆) δ −3.54 (s, 2 H), 3.79 (s, 12 H), 8.55(s 4 H), 9.28 (d, 4 H), 11.00 (s, 2 H).

4. [5,15-Bis(1,3-dimethylimidazolium-2-yl)porphyrinato]manganese (III)Trichloride (36).

Porphyrin 35 (150 mg, 0.198 mmol) was dissolved in water (50 mL) and thesolution pH was adjusted to pH=12 with 6N NaOH. Manganese chloride (375mg, 2.98 mmol) was added and the reaction mixture was stirred for 30min. The solution was filtered on a fine fritted filter funnel, the pHof the filtrate was adjusted to pH=4 (1N HCl) and the solution wasfiltered. Purification of the solid filter cake by the doubleprecipitation method and drying provided porphyrin 36 (25.5 mg, 20%) asa solid: mp>300° C.; UV-vis λ_(max)=447.5 nm; ε=8.66×10⁴ L/cm-mol; APIMS m/z=554 [C₃₀H₂₆MnN₈+H]⁺².

X.[5,10,15,20-Tetrakis(1,4,5-trimethylimidazol-2-yl)porphyrinato]-manganese(III) Chloride (39) and[5,10,15,20-Tetrakis(1,3,4,5-tetramethyl-imidazolium-2-yl)porphyrinato]manganese(III) Pentachloride (41).

1. [5,10,15,20-Tetrakis(1,4,5-trimethylimidazol-2-yl)porphyrin (38).

1,4,5-Trimethylimidazole-2-carboxaldehyde (37, 750 mg, 5.42 mmol),prepared according to literature procedure (Alcalde, E. et al.,Tetrahedron 52:15171-15188 (1996)), was dissolved in propionic acid (120mL) in a 250 mL three neck round-bottom flask equipped with athermometer and a condenser. The solution was heated to reflux thenpyrrole (0.38 mL, 5.42 mmol) was added. The reaction mixture was heatedat reflux for an additional 5 h, then cooled to room temperature whileexposed to air overnight. The propionic acid was removed by vacuumdistillation yielding a dark solid residue which was adsorbed ontosilica gel. Purification by column chromatography (gradient elution5-10% MeOH/CH₂Cl₂) provided porphyrin 38 as a mixture of atropisomers(108 mg, 10.7%). ¹H NMR (300 MHz, CDCl₃)*−2.90, −2.85, −2.78 (3 s, 2H,atropisomer NH), 2.50 (s, 12 H), 2.57 (s, 12 H), 3.15-3.42 (multiple s,12 H, atropisomer N—CH₃), 8.91 (multiple s, 8 H, atropisomer).

2.[5,10,15,20-Tetrakis(1,4,5-trimethylimidazol-2-yl)porphyrinato]manganese(III) Chloride (39).

Porphyrin 38 (40 mg, 0.05 mmol) was dissolved in MeOH (7 mL) in a 25 mLround-bottom flask equipped with a condenser. Manganese (II) chloride(101 mg, 0.81 mmol) was added and the reaction mixture was heated underreflux for 2 h. Air was bubbled into the reaction mixture for 20 minthen methanol was evaporated in vacuo. Purification of the residue bycolumn chromatography provided porphyrin 39 as a black solid (12 mg,27%): mp>300° C.; UV-vis 8_(max)=474.5 nm, ,=9.74×10⁴ L/cm-mol; API MSm/z=795[C₄₄H₄₄MnN₁₂]⁺.

3. [5,10,15,20-Tetrakis(1,3,4,5-tetramethylimidazolium-2-yl)porphyrinTetraiodide (40).

Porphyrin 38 (40 mg, 0.05 mmol) was dissolved in DMF (5 mL) in a sealedtube reactor. Methyl iodide (1 mL, 16 mmol) was added and the sealedtube heated at 60° C. overnight. Dilution of the reaction mixture withEtOAc (100 mL) resulted in the precipitation of crude product 40 whichwas collected by vacuum filtration then purified by columnchromatography to provide porphyrin 40 as a dark purple solid (25 mg,35%): ¹H NMR (300 MHz, DMSO-d₆)*−3.20 (s, 2 H), 2.72 (s, 24 H), 3.58 (s,24 H), 9.40 (s, 8 H).

4.[5,10,15,20-Tetrakis(1,3,4,5-tetramethylimidazolium-2-yl)porphyrinato]-manganese(III) Pentachloride (41).

Porphyrin 40 (25 mg, 0.02 mmol) was dissolved in methanol (7 mL) in around-bottomed flask (25 mL). Manganese (II) chloride (50 mg, 0.4 mmol)was added and the reaction mixture was heated at 60° C. for 6 h. NaOH(2N, 2 drops) was added and the reaction mixture stirred for anadditional hour. The reaction mixture was filtered through celite andwashed through with MeOH. Analysis of the filtrate by UV-visspectroscopy indicated that the reaction was incomplete. The solvent wasevaporated off and the residue redissolved in MeOH (7 mL), then MnCl₂(50 mg, 0.4 mmol) was added and the reaction mixture was heated at 60°C. for 3 h. Air was bubbled into the reaction mixture for 20 min. Thereaction mixture was filtered over celite and washed with MeOH.Evaporation of the solvents in vacuo provided a brown residue.Purification of the product by the double precipitation method providedporphyrin 41 (10 mg, 51%) as a brown solid: mp>300° C.; UV-vis8_(max)=451.5 nm, ,=9.29×10⁴ L/cm-mol.

XI.[5,10,15,20-Tetrakis(4-methyl-1,2,4-triazol-3-yl)porphyrinato]manganese(III) Chloride (44).

1. 5,10,15,20-Tetrakis(4-methyl-1,2,4-triazol-3-yl)porphyrin (43).

4-Methyl-1,2,4-triazole-2-carboxaldehyde (42, 1.06 g, 9.5 mmol),prepared according to literature procedure (Moderhack, D.; Hoppe-Tichy,T. J. Prakt. Chem/Chem-Ztg. 1996, 338(2), 169-171), was dissolved inpropionic acid (180 mL) in a 250-mL three-neck round bottom flaskcovered with foil and equipped with a condenser. The solution was heatedto reflux, and then pyrrole (0.66 mL, 9.5 mmol) was added. The reactionmixture was stirred at reflux for an additional 2.5 h. The reaction wasthen cooled to room temperature while exposed to air over 2 days.Evaporation of the propionic acid under reduced pressure provided a darkresidue which was adsorbed onto silica gel. Repeated purification bycolumn chromatography (gradient elution, CHCl₃, MeOH, concentratedNH₄OH, EtOAc) provided porphyrin 43 (219 mg, 14.6%) as a solid mixtureof atropiosomers: ¹H NMR (300 MHz, DMSO-d₆) δ −3.36, −3.13, −3.09 (3 s,2 H, atropisomer NH), 3.43-3.64 (multiple s, 12 H, atropisomer N—CH₃),9.03 (broad s, 8 H), 9.20 (s, 4 H).

2.[5,10,15,20-Tetrakis(4-methyl-1,2,4-triazol-3-yl)porphyrinato]manganese(III) Chloride (44).

Porphyrin 43 (77 mg, 0.12 mmol) was dissolved in DMF (30 mL) in a 100-mLround bottom flask equipped with a condenser. Manganese (II) chloride(156 mg, 1.24 mmol) was added and the reaction was heated at 130° C.overnight. The reaction mixture was exposed to a stream of air as itcooled to room temperature. The porphyrin precipitated out upon theaddition of CH₂Cl₂ (5-10 mL). The solids were filtered and washed withEtOH and CH₂Cl₂ to provide porphyrin 44 (45 mg, 51%) as a brown solid:mp>300° C.; UV-vis λ_(max)=452.5 nm; ε=8.10×10⁴ L/cm-mol; FAB-MS m/z=787[C₃₂H₂₄MnN₁₈]⁺.

XII.[5,15-Bis(trifluoromethyl)-10,20-bis(imidazol-2-yl)porphyrinato]-manganese(III) Chloride (47).

1. 5,15-Bis(trifluoromethyl)-10,20-bis(imidazol-2-yl)porphyrin (46).

In a foil-covered 1-L three-neck round bottom flask, equipped with amagnetic stirrer and a N₂ outlet, was added dipyrromethane 45 (1.13 g,5.28 mmol), 1 -methylimidazole-2-carboxaldehyde (20, 582 mg, 5.28 mmol),sodium chloride (32 mg, 0.54 mmol) and CH₂Cl₂ (530 mL). The reactionmixture was stirred for 10 min, then TFA (2.40 mL, 31.1 mmol) was added.After a stirring period of 105 min, DDQ (1.81 g, 7.97 mmol) was added,and the mixture was stirred overnight. The solvent was removed by rotaryevaporation, and the crude residue was adsorbed onto silica gel (3 g).Purification by column chromatography (gradient elution, 5-10%MeOH/CH₂Cl₂) provided porphyrin 46 (455 mg, 34%) as a black solid: ¹HNMR (300 MHz, CDCl₃) δ −2.87 (s, 2 H), 3.56 (m, 6 H), 7.85 (d, 2 H),8.05 (d, 2 H), 8.99 (m, 4 H), 9.81 (m, 4 H); API-MS m/z=607[C₃₀H₂₀F₆N₈+H]⁺.

2.[5,15-Bis(trifluoromethyl)-10,20-bis(imidazol-2-yl)porphyrinato]manganese(III) Chloride (47).

A solution of free porphyrin 46 (113 mg, 0.186 mmol) and MnCl₂ (360 mg,2.86 mmol) in DMF (15 mL) was warmed to 120° C. for 6 h. The mixture wascooled to room temperature while exposed to a stream of air, thenconcentrated by rotary evaporation. The crude residue was dissolved in10% MeOH/CH₂Cl₂ (100 mL), then adsorbed onto silica gel (1 g).Purification by column chromatography (10% MeOH/CH₂Cl₂) providedporphyrin 47 (45 mg, 35%) as a dark green solid: mp>300° C.; UV-visλ_(max)=456.5 nm; ε=1.98×10⁴ L/cm-mol; API-MS m/z=659 [C₃₀H₁₈F₆MnN₈]⁺.

XIII. [5,10,15,20-Tetrakis(1-methylpyrazol-4-yl)porphyrinato]manganese(III) Chloride (50) and[5,10,15,20-Tetrakis(1,2-dimethylpyrazolium-4-yl)porphyrinato]-manganese(III) Pentachloride (52).

1. 5,10,15,20-Tetrakis(1-methylpyrazol-4-yl)porphyrin (49).

To a refluxing solution of propionic acid (200 mL) and1-methylpyrazole-4-carboxaldehyde (48, 0.92 g, 8.32 mmol), preparedaccording to literature procedure (Finar, I. L.; Lord, G. H. J. Chem.Soc. 1957, 3314-3315), was added pyrrole (0.63 mL, 8.32 mmol). Thereaction was covered with foil and was heated under reflux for 3.5 h.Upon cooling the reaction mixture was exposed to air overnight. Thepropionic acid was then removed by vacuum distillation. The cruderesidue was dissolved in 5% MeOH/CH₂Cl₂, then adsorbed onto silica gel(5.3 g). Purification by column chromatography (5% MeOH/CH₂Cl₂) providedporphyrin 49 as a purple solid (231 mg, 17.5%): ¹H NMR (300 MHz,DMSO-d₆) δ −2.74 (s, 2 H), 4.28 (s, 12 H), 8.31 (s, 4 H), 8.67 (s, 4 H),9.16 (s, 8 H).

2. [5,10,15,20-Tetrakis(1-methylpyrazol-4-yl)porphyrinato]manganese(III) Chloride (50).

Porphyrin 49 (50 mg, 7.93×10⁻² mmol) was dissolved in DMF (10 mL) in a25-mL round bottom flask equipped with a condenser. Manganese (II)chloride (150 mg, 1.19 mmol) was added and the reaction was heated at125° C. for 4 h. A stream of air was introduced and the reaction heatedfor an additional 2 h. The reaction was diluted with EtOAc (100 mL) andthe crude product was collected by vacuum filtration. Purification ofthe residue by column chromatography (10% MeOH/CH₂Cl₂) followed bycounterion exchange provided porphryin 50 as a green solid (15 mg, 25%):mp>300° C.; UV-vis λ_(max)=471.0 nm, ε=9.55×10⁴ L/cm-mol; API MS m/z=683[C₃₆H₂₈MnN₁₂]⁺.

3. 5,10,15,20-Tetrakis(1,2-dimethylpyrazolium-4-yl)porphyrinTetrachloride (51).

Porphyrin 49 (200 mg, 0.32 mmol) was dissolved in DMF (15 mL) in asealed tube reactor. Methyl iodide (2 mL, 32 mmol) was added and thesealed tube heated at 125° C. for 6 h. Dilution of the reaction mixturewith EtOAc resulted in the precipitation of crude product which wascollected by vacuum filtration and initially purified by columnchromatography (8:1:1 CH₃CN/water/saturated KNO₃). Further purificationby the double precipitation method provided porphyrin 51 as a darkpurple solid (45 mg, 17%): ¹H NMR (300 MHz, DMSO-d₆) δ −3.16 (s, 2 H),4.55 (s, 24 H), 9.45 (s, 8 H), 9.50 (s, 8 H).

4.[5,10,15,20-Tetrakis(1,2-dimethylpyrazolium-4-yl)porphyrinato]manganese(III) Pentachloride (52).

Porphyrin 51 (40 mg, 4.80×10⁻² mmol) was dissolved in water (10 mL).Manganese (II) chloride (90 mg, 0.72 mmol) was added and the reactionwas heated at 50° C. Analysis of the reaction mixture by UV-visspectroscopy showed incomplete reaction. Additional MnCl₂ (210 mg, 1.67mmol) was added and heating of the reaction mixture was continued untilcompletion of reaction was indicated by UV-vis analysis. Filtrationfollowed by purification of the product by the double precipitationmethod provided porphyrin 52 (25 mg, 57%) as a brown solid: mp>300° C.;UV-vis λ_(max)=461.0 nm, ε=7.82×10⁴ L/cm-mol; API MS m/z=683[C₄₀H₄₀MnN₁₂−4CH₃]⁺.

XIV.[5,10,15,20-Tetrakis(1,3-dimethylimidazolium-5-yl)porphyrinato]manganese(III) Pentachloride (56).

1. 5,10,15,20-Tetrakis(1-methylimidazol-5-yl)porphyrin (54).

To a refluxing solution of propionic acid (400 mL) and1-methylimidazole-5-carboxaldehyde (53, 2.0 g, 18.16 mmol), preparedaccording to literature procedure (Dener, J. M.; Zhang, L-H.; Rapoport,H. J. Org. Chem. 1993, 58, 1159-1166), was added pyrrole (1.26 mL, 18.16mmol). The reaction was covered with foil then heated under reflux for 5h. Upon cooling, the reaction mixture was exposed to air for 60 h. Thepropionic acid was then removed by vacuum distillation. The residue wasdissolved in 10% MeOH/CH₂Cl₂, then adsorbed onto silica gel (6 g).Purification by column chromatography (gradient elution, 5-10%MeOH/CH₂Cl₂) provided porphyrin 54 as a purple solid (600 mg, 21%): ¹HNMR (300 MHz, CDCl₃) δ −2.80, −2.75 (2 s, 2 H, atropisomer NH),3.42-3.58 (multiple s, 12 H, atropisomer N—CH₃), 7.87-7.98 (multiple s,4 H, atropisomer), 8.06 (s, 4 H), 8.95-8.99 (multiple s, 8 H,atropisomer).

2. 5,10,15,20-Tetrakis(1,3-dimethylimidazolium-5-yl)porphyrinTetraiodide (55).

Porphyrin 54 (395 mg, 0.63 mmol) was dissolved in DMF (15 mL) in asealed tube reactor. Methyl iodide (2 mL, 32 mmol) was added and thesealed tube was heated at 100° C. overnight. Dilution of the reactionmixture with EtOAc (200 mL) resulted in the precipitation of the crudeproduct which was collected by vacuum filtration. Purification by columnchromatography (8:1:1 CH₃CN/water/saturated KNO₃) provided porphyrin 55(250 mg, 33%) as a dark purple solid: ¹H NMR (300 MHz, DMSO-d₆) δ −3.25(s, 2 H), 3.46-3.64 (multiple s, 12 H, atropisomer), 4.30 (s, 12 H),8.68 (s, 4 H), 9.48 (s, 8 H), 9.78 (s,4 H).

3.[5,10,15,20-Tetrakis(1,3-dimethylimidazolium-5-yl)porphyrinato]-manganese(III) Pentachloride (56).

Porphyrin 55 (200 mg, 0.17 mmol) was dissolved in methanol (100 mL).Manganese (II) chloride (315 mg, 2.50 mmol) was added and an air streamintroduced into the reaction mixture. The pH of the solution wasmaintained at 8 by the dropwise addition of 6N NaOH over the period ofthe reaction, after which time the pH was adjusted to 5 with 6N HCl. Thereaction was filtered on a fritted funnel. Purification of the productby the double precipitation method provided porphyrin 56 (63 mg, 41%) asa brown solid: mp>300° C.; UV-vis λ_(max)=454.0 nm, ε=1.23×10⁵ L/cm-mol.

XV.[5,15-Bis(4-fluorophenyl)-10,20-bis(1-methylimidazol-2-yl)porphyrinato]-manganese(III) Chloride (59) and[5,15-Bis(4-fluorophenyl)-10,20-bis(1,3-dimethylimidazolium-2-yl)porphyrinato]manganese(III) Trichloride (61).

1. 5,15-Bis(4-fluorophenyl)-10,20-bis(1-methylimidazol-2-yl)porphyrin(58).

In a foil-covered 1 -L three-neck round bottom flask, equipped with amagnetic stirrer and a N₂ outlet, was added dipyrromethane 25 (1.00 g,4.43 mmol), 4-fluoro-benzaldehyde (57, 550 mg, 4.43 mmol), sodiumchloride (30 mg, 0.5 mmol) and CH₂Cl₂ (450 mL). The reaction mixture wasstirred for 10 min, then TFA (2.0 mL, 26 mmol) was added. After astirring period of 105 min, DDQ (1.51 g, 6.65 mmol) was added, and themixture was stirred overnight. The solvent was removed by rotaryevaporation, and the crude residue was adsorbed onto silica gel (3 g).Purification by column chromatography (gradient elution, 5-10%MeOH/CH₂Cl₂) provided porphyrin 58 (229 mg, 16%) as a black solid: ¹HNMR (300 MHz, DMSO-d₆) δ −3.05 (s, 2 H), 3.70, 3.72 (2 s, 6 H,atropisomer N—CH₃), 7.73 (m, 8 H), 8.19 (s, 2 H), 8.30 (m, 4 H), 9.02(m, 6 H); API-MS m/z=659 [C₄₀H₂₈F₂N₈+H]⁺.

2.[5,15-Bis(4-fluorophenyl)-10,20-bis(1-methylimidazol-2-yl)porphyrinato]-manganese(III) Chloride (59).

Porphyrin 58 (85 mg, 0.13 mmol) was dissolved in DMF (7 mL) in a 50-mLround bottom flask equipped with a condenser. Manganese (II) chloride(215 mg, 1.71 mmol) was added and the reaction was heated at 120° C. for3.5 h. The reaction was cooled to room temperature then concentrated byrotary evaporation. The crude residue was dissolved in 20% MeOH/CH₂Cl₂(100 mL) and adsorbed onto silica gel (2 g). Purification by columnchromatography (gradient elution, 3-8% MeOH/CH₂Cl₂) provided porphryin59 as a green solid (15 mg, 16%): mp>300° C.; UV-vis λ_(max)=463.0 nm,ε=4.05×10⁴ L/cm-mol; API MS m/z=711 [C₄₀H₂₆F₂MnN₈]⁺.

3. 5,15-Bis(4-fluorophenyl)-10,20-bis(1,3-imidazolium-2-yl)porphyrinDichloride (60).

Porphyrin 58 (170 mg, 0.26 mmol) was dissolved in DMF (7 mL) in a sealedtube reactor. Methyl iodide (6 mL, 96 mmol) was added and the sealedtube was heated at 100° C. overnight. The mixture was cooled to roomtemperature and concentrated by rotary evaporation. The residue wasprecipitated as the chloride salt from acetone by the addition of Bu₄NClsolution in acetone (0.3 g/mL). The solid was collected on a frittedfunnel, washed with copious quantities of acetone, and dried undervacuum at room temperature to provide porphyrin 60 as a dark purplesolid (196 mg). The product was used without further purification.

4.[5,15-Bis(4-fluorophenyl)-10,20-bis(1,3-dimethylimidazolium-2-yl)porphyrinato]manganese(III) Trichloride (61).

Porphyrin 60 (196 mg, est. 0.26 mmol) dissolved in MeOH (30 mL) wasslowly warmed to 55° C. then Mn(OAc)₃•2 H₂O (694 mg, 2.59 mmol) wasadded. After a stirring period of 3 h, the mixture was cooled to roomtemperature, filtered through Celite and concentrated by rotaryevaporation. The residue was purified by the double precipitation methodto provide porphyrin 61 (102 mg, 46% over two steps) as a dark greensolid: mp>300° C., UV-vis λ_(max)=458.0 nm; ε=1.30×10⁴ L/cm-mol; ES-MSm/z=967 [(C₄₂H₃₂F₂MnN₈)⁺³+2 (CF₃CO₂ ⁻)]⁺.

XVI.[5,10,15,20-Tetrakis(1,3-diethylimidazolium-2-yl)porphyrinato]manganese(III) Pentachloride (65).

1. 5,10,15,20-Tetrakis(1-ethylimidazol-2-yl)porphyrin (63).

To a refluxing solution of propionic acid (450 mL) and1-ethylimidazole-2-carboxaldehyde (62, 2.5 g, 20.0 mmol, prepared in asimilar manner as the methyl imidazole derivative 20) was added pyrrole(1.40 mL, 20.0 mmol). The reaction was covered in foil then heated underreflux for 5 h. Upon cooling, the reaction mixture was exposed to airovernight. The propionic acid was then removed by vacuum distillation.Repeated purification by column chromatography (gradient elution,CHCl₃/MeOH/ concentrated NH₄OH/EtOAc) provided porphyrin 63 as a purplesolid (281 mg, 8.1%): ¹H NMR (300 MHz, CDCl₃) δ −2.95, −2.90, −2.87 (3s, 2 H, atropisomer NH), 0.85-1.25 (multiple t, 12 H, atropisomer CH₃),3.61-3.88 (multiple q, 8 H, atropisomer CH₂), 7.55 (d, 4 H), 7.70 (d, 4H), 8.98 (multiple s, 8 H, atropisomer).

2. 5,10,15,20-Tetrakis(1,3-diethylimidazolium-2-yl)porphyrin Tetraiodide(64).

Porphyrin 63 (106 mg, 0.15 mmol) was dissolved in DMF (5 mL) in a sealedtube reactor. Ethyl iodide (2.0 mL, 25 mmol) was added and the sealedtube was heated at 65° C. for 6 h. Dilution of the reaction mixture withEtOAc (100 mL) resulted in the precipitation of the crude product whichwas collected by vacuum filtration, washed with chloroform and thenpurified by column chromatography (8:1:1 CH₃CN/water/saturated KNO₃) toprovide porphyrin 63 (140 mg, 69%) as a dark purple solid: ¹H NMR (300MHz, DMSO-d₆) δ −3.22 (s, 2 H), 1.17 (t, 24 H), 4.01 (s, 16 H), 8.70 (s,8 H), 9.43 (s, 8 H).

3.[5,10,15,20-Tetrakis(1,3-diethylimidazolium-2-yl)porphyrinato]-manganese(III) Pentachloride (65).

Porphyrin 64 (106 mg, 8.09×10⁻² mmol) was dissolved in methanol (15 mL)then Mn(OAc)₃•2 H₂O (216 mg, 0.81 mmol) was added and the reactionheated at 55° C. for 2.5 h. The reaction was filtered through celite andthen evaporated in vacuo. Purification of the product by the doubleprecipitation method provided porphyrin 65 (65 mg, 78%) as a brownsolid: mp>300° C., UV-vis λ_(max)=446.5 nm, ε=1.35×10⁵ L/cm-mol; ES-MSm/z=1307 [(C₄₈H₅₆MnN₁₂)⁺⁵+4(CF₃CO₂ ⁻)]⁺.

XVII.[5,10,15,20-Tetrakis(1-ethyl-3-methylimidazolium-2-yl)porphyrinato]-manganese(III) Pentachloride (67).

1. 5,10,15,20-Tetrakis(1-ethyl-3-methylimidazolium-5-yl)porphyrinTetrachloride (66).

Porphyrin 21 (371 mg, 0.588 mmol) was dissolved in DMF (8 mL) in asealed tube reactor. Ethyl iodide (7 mL, 88 mmol) was added and thesealed tube was heated at 60° C. overnight. The mixture was cooled toroom temperature and concentrated by rotary evaporation. The residue wasdissolved in water (20 mL) and purified by the double precipitationmethod to provide porphyrin 66 (349 mg, 67%) as a dark purple solid: ¹HNMR (300 MHz, DMSO-d₆) δ −3.23 (s, 2 H), 1.17 (m, 12 H), 3.77 (m, 12 H),4.03 (m, 8 H), 7.01, 7.18, 7.35 (multiple s, 8 H), 8.63 (d, 4 H), 9.36(s, 4 H).

2.[5,10,15,20-Tetrakis(1-ethyl-3-methylimidazolium-2-yl)porphyrinato]-manganese(III) Pentachloride (67).

Porphyrin 66 (340 mg, 0.39 mmol) was dissolved in methanol (45 mL) thenMn(OAc)₃•2 H₂O (680 mg, 2.53 mmol) was added, and the mixture wasstirred at 55° C. for 3.5 h. The mixture was cooled to room temperature,filtered through Celite (to remove insoluble solids), and concentratedby rotary evaporation. The residue was purified by the doubleprecipitation method to provide porphyrin 67 (324 mg, 85%) as a brownsolid: mp>300° C.; UV-vis λ_(max)=446.5 nm; ε=5.11×10⁴ L/cm-mol; ES-MSm/z=1251 [(C₄₄H₄₈MnN₁₂)⁺⁵+4 (CF₃CO₂ ⁻)]⁺.

EXAMPLE 2 Treatment of Bronchopulmonary Dysplasia Using Aeol-V (10123)

Neonatal baboons were delivered prematurely by Caesarian section andthen treated either with 100% oxygen or only sufficient PRN FIO₂ tomaintain adequate arterial oxygenation. To establish the model, thirteen100% oxygen treated animals and seven PRN control animals were studied.Treatment with 100% oxygen results in extensive lung injury manifestedby days 9 or 10 of exposure and characterized by delayedalveolarization, lung parenchymal inflammation, and poor oxygenation.This is characteristic of the human disease, bronchopulmonary dysplasia,and is thought to be mediated, at least in part, by oxidative stress onthe developing neonatal lung. In a first trial of Aeol-V, a neonatalbaboon was delivered at 140 days gestation and placed in 100% oxygen.The animal received 0.25 mg/kg/24 hr given i.v. in a continuous infusionover the entire 10 day study period (see FIG. 2). This animal showedmarked improvement of the oxygenation index. There was no evidence ofclinical decompensation of the lungs at days 9 and 10. This suggeststhat Aeol-V can be used to treat oxidant stress in the prematurenewborn.

All documents cited above are hereby incorporated in their entirety byreference.

One skilled in the art will appreciate from a reading of this disclosurethat various changes in form and detail can be made without departingfrom the true scope of the invention.

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof.
 2. A compound having theformula:

or a pharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition comprising the compound of claim 1 and an excipient.
 4. Apharmaceutical composition comprising the compound of claim 2 and anexcipient.
 5. A method of treating diabetes mellitus Type I or diabetesmellitus Type II in a subject, said method comprising the step of:administering an effective amount of a composition including at leastone compound having the formula

or pharmaceutically acceptable salts thereof.